Endocannabinoid reuptake inhibitor explained

Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.[1]

Pharmacology

The method of transport of endocannabinoids through the cell membrane and cytoplasm to their respective degradation enzymes has been rigorously debated for nearly two decades, and a putative endocannabinoid membrane transporter was proposed.[2] However, as lipophilic molecules endocannabinoids readily pass through the cell lipid bilayer without assistance and would more likely need a chaperone through the cytoplasm to the endoplasmic reticulum where the enzyme FAAH is located. More recently fatty acid-binding proteins (FABPs) and heat shock proteins (Hsp70s) have been described and verified as such chaperones, and their inhibitors have been synthesized.[3] [4] The inhibition of endocannabinoid reuptake raises the amount of those neurotransmitters available in the synaptic cleft and therefore increases neurotransmission. Following the increase of neurotransmission in the endocannabinoid system is the stimulation of its functions which, in humans, include: suppression of pain perception (analgesia), increased appetite, mood elevation and inhibition of short-term memory.[5] [6]

Examples of eCBRIs

See also

Notes and References

  1. Costa B, Siniscalco D, Trovato AE, Comelli F, Sotgiu ML, Colleoni M, Maione S, Rossi F, Giagnoni G . AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain . Br. J. Pharmacol. . 148 . 7 . 1022–32 . 2006 . 16770320 . 1751928 . 10.1038/sj.bjp.0706798 .
  2. Nicolussi . Simon . Gertsch . Jürg . 2015 . Endocannabinoid Transport Revisited . Vitamins & Hormones . 98 . 14 . 441–485 . 10.1016/bs.vh.2014.12.011 . 25817877 . 2021-01-17.
  3. Berger WT, Ralph BP, Kaczocha M, Sun J, Balius TE, Rizzo RC, Haj-Dahmane S, Ojima I, Deutsch DG . Targeting fatty acid binding protein (FABP) anandamide transporters - a novel strategy for development of anti-inflammatory and anti-nociceptive drugs . PLOS ONE . 7 . 12 . e50968 . 2012 . 23236415 . 3517626 . 10.1371/journal.pone.0050968 . 2012PLoSO...750968B . free .
  4. Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins . 2009 . Chemistry & Biology . 16 . 6 . 624–632 . Oddi . S. . Fezza . F. . Pasquariello . N. . D'Agostino . A. . Catanzaro . G. . De Simone . C. . Rapino . C. . Finazzi-Agro . A. . Maccarrone . M. . 19481477 . 10.1016/j.chembiol.2009.05.004 .
  5. Web site: Endocannabinoid System .
  6. Chicca . Andrea . Nicolussi . Simon . Bartholomäus . Ruben . Blunder . Martina . Aparisi Rey . Alejandro . Petrucci . Vanessa . Reynoso-Moreno . Ines del Carmen . Viveros-Paredes . Juan Manuel . Dalghi Gens . Marianela . Lutz . Beat . Schiöth . Helgi B. . Soeberdt . Michael . Abels . Christoph . Charles . Roch-Philippe . Altmann . Karl-Heinz . Gertsch . Jürg . Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake . Proceedings of the National Academy of Sciences of the United States of America . 20 June 2017 . 114 . 25 . E5006–E5015 . 10.1073/pnas.1704065114 . 28584105 . 5488949 . 2017PNAS..114E5006C . 0027-8424. free .
  7. Glaser ST, Kaczocha M, Deutsch DG . Aug 2005 . Anandamide transport: a critical review . Life Sci . 77 . 14. 1584–604 . 15979096 . 10.1016/j.lfs.2005.05.007 .
  8. Nicolussi S, Viveros-Paredes JM, Gachet MS, Rau M, Flores-Soto ME, Blunder M, Gertsch J . Feb 2014 . Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice . Pharmacol. Res. . 80 . 52–65 . 24412246 . 10.1016/j.phrs.2013.12.010 .
  9. Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L, Simmons RM, Li D, Iyengar S, Felder CC . 2005. Identification of a high-affinity binding site involved in the transport of endocannabinoids. . . 102. 49. 17852–7. 10.1073/pnas.0507470102 . 16314570 . 1295594 . free.
  10. Web site: SYT 510 . AdisInsight . 22 January 2024 . 9 August 2024.
  11. Chicca A, Nicolussi S, Bartholomäus R, Blunder M, Aparisi Rey A, Petrucci V, Reynoso-Moreno ID, Viveros-Paredes JM, Dalghi Gens M, Lutz B, Schiöth HB, Soeberdt M, Abels C, Charles RP, Altmann KH, Gertsch J . 2017. Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake . Proc Natl Acad Sci U S A . 55 . 25. E5006–E5015. 10.1073/pnas.1704065114 . 28584105 . 5488949 . 2017PNAS..114E5006C. free.
  12. Nicolussi S, Chicca A, Soeberdt M, Abels C, Viveros.Paredes JM, Aparisi-Rey A, Lutz B, Gertsch J. WOBE437 - Prototype of a novel class of potent, selective endocannabinoid reuptake inhibitors. BPS 6th Eur Workshop on Cannabinoid Research 2013.

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